This proposal is focused on complementary and alternative approaches to medicine geared toward understanding the molecular mechanisms of macrophage activation. It addresses the possibility that omega-3 fatty acids, like those found in fish oil, modulate inflammation by promoting alternative activation. The nuclear hormone receptor PPAR gamma acts as a lipid-sensor and likely directs this modulation of macrophage activation phenotypes by omega-3 fatty acids. Furthermore, PPAR gamma is a well recognized transcription factor that has been shown to regulate several aspects of macrophage cellular metabolism. However, the regulatory roles of fatty acids in macrophage inflammation are poorly understood. The studies herein will help to further investigate cellularly, molecularly, and genetically, how fatty acids may alleviate chronic diseases symptoms. In specific aim 1 we will test the hypothesis that dietary enrichment with seed oil from Echium plantagineum has the ability to ameliorate inflammation similar to fish oil in a mouse model of atherosclerosis and chronic inflammation. This will serve as an in vivo approach to ask the question if supplementation with a botanical source of omega-3 fatty acids causes alternative activation in macrophages, as a means to reduce pro-inflammatory phenotypes and responses. In specific aim 2 we will use genomic, cell based and molecular approaches to address the role of PPAR gamma in the macrophage response to omega-3 fatty acids. We will systematically look at the coordinate roles of PPAR gamma transcriptional activation and inflammatory gene transrepression pathways in modulating omega-3 fatty acid responses. We also test the hypothesis that the shifting of macrophage phenotypes caused by omega-3 fatty acid enrichment is dependent on the enzymatic activity of 12/15-lipoxygenase, a lipid-peroxidizing enzyme. It is well established that 12/15-lipoxygenase produces fatty acid-derived ligands that may serve to activate PPAR gamma endogenously. The significance of this project is two-fold. First, it lies in the determination of whether echium oil, a botanical source of omega-3 fatty acids, possesses the anti-inflammatory potential offish oil. Secondly, it will provide novel mechanistic data on the role of n-3 PUFAs in ameliorating inflammaiton and whether this occurs through priming macrophages toward inflammationresolving, alternatively activated phenotypes, a field in which strong support is lacking. If our hypothesis is correct, the results will support the rationale for inclusion of stearidonic acid-enriched botanical oils, as from Echium plantagineum, in food products providing a source of n-3 PUFAs that could reduce inflammation in the population, and decrease the risk of atherosclerosis and other chronic diseases.